Effect of Placenta-Derived Mesenchymal Stem Cells in a Dementia Rat Model via Microglial Mediation: a Comparison between Stem Cell Transplant Methods

Abstract

PurposeLoss of cholinergic neurons in the hippocampus is a hallmark of many dementias. Administration of stem cells as a therapeutic intervention for patients is under active investigation, but the optimal stem cell type and transplantation modality has not yet been established. In this study, we studied the therapeutic effects of human placenta-derived mesenchymal stem cells (pMSCs) in dementia rat model using either intracerebroventricular (ICV) or intravenous (IV) injections and analyzed their mechanisms of therapeutic action.Materials and MethodsDementia modeling was established by intraventricular injection of 192 IgG-saporin, which causes lesion of cholinergic neurons. Sixty-five male Sprague-Dawley rats were divided into five groups: control, lesion, lesion+ICV injection of pMSCs, lesion+IV injection of pMSCs, and lesion+donepezil. Rats were subjected to the Morris water maze and subsequent immunostaining analyses.ResultsBoth ICV and IV pMSC administrations allowed significant cognitive recovery compared to the lesioned rats. Acetylcholinesterase activity was significantly rescued in the hippocampus of rats injected with pMSCs post-lesion. Choline acetyltransferase did not co-localize with pMSCs, showing that pMSCs did not directly differentiate into cholinergic cells. Number of microglial cells increased in lesioned rats and significantly decreased back to normal levels with pMSC injection.ConclusionOur results suggest that ICV and IV injections of pMSCs facilitate the recovery of cholinergic neuronal populations and cognitive behavior. This recovery likely occurs through paracrine effects that resemble microglia function rather than direct differentiation of injected pMSCs into cholinergic neurons.

Focused ultrasound-induced blood-brain barrier opening improves adult hippocampal neurogenesis and cognitive function in a cholinergic degeneration dementia rat model

“…The performance of all rats in all groups gradually improved across 5 days of MWM training, suggesting that rats with cholinergic dysfunction have a similar level of learning capacity and escape latency compared with wild-type rats (Fig. 6) [34, 35]. In the probe test, when compared with the control and FUS groups, the SAP group displayed a diminished MWM performance 72 h after final training, as measured by the number of crossing over the platform area and time spent, which complements the findings of previous studies [33–36, 44].…”

Molecular and Cellular Mechanisms Responsible for Beneficial Effects of Mesenchymal Stem Cell-Derived Product “Exo-d-MAPPS” in Attenuation of Chronic Airway Inflammation

“…The beneficial effects of MSCs were mainly attributed to the activity of MSC-derived products (conditioned medium (MSC-CM) and exosomes (MSC-Exos)): nanosized extracellular vesicles that, in a paracrine and endocrine manner, delivered proteins, lipids, DNA fragments, and mRNA to the immune, endothelial, and alveolar epithelial cells modulating their function [20]. Several lines of evidence suggested that MSCs derived from placental tissues (PL-MSCs) had superior biological properties compared to MSCs derived from adult tissues [21][22][23][24]. In line with these findings, we recently developed the "Exosome-derived Multiple Allogeneic Protein Paracrine Signaling (Exo-d-MAPPS)," a PL-MSC-derived product whose activity is based on exosomes, growth factors, and immunomodulatory cytokines capable of attenuating inflammation and promoting the regeneration of injured tissues [25].…”

Therapeutic Potential of “Exosomes Derived Multiple Allogeneic Proteins Paracrine Signaling: Exosomes d-MAPPS” is Based on the Effects of Exosomes, Immunosuppressive and Trophic Factors

“…Moreover, clonal subpopulations of PL-MSCs have been attributed with the potential to differentiate into tissues from all three germ layers. Accordingly, due to their capacity for neuronal differentiation, PL-MSCs have been proposed as one of the main candidates for stem cell therapy of multiple sclerosis, nerve injuries, and sensorineural hearing loss (23)(24)(25)(26).…”